In silico pharmacology最新文献

{"title":"Structural basis for Kisspeptin-10 selectivity toward KISS1R: computational insights.","authors":"Maria A Netesa, Sarng S Pyurveev, Andrei A Lebedev, Eugenii R Bychkov, Ekaterina V Skorb, Sergey Shityakov, Petr D Shabanov","doi":"10.1007/s40203-026-00726-0","DOIUrl":"10.1007/s40203-026-00726-0","url":null,"abstract":"<p><strong>Abstract: </strong>Kisspeptin-10 (KP-10), the bioactive core fragment of kisspeptin neuropeptides, has emerged as a modulator of reward-related behaviors beyond its canonical role in reproductive neuroendocrinology. While behavioral studies indicate that KP-10 promotes impulsive and compulsive-like phenotypes in rodent models, the molecular mechanisms underlying these effects remain unclear. This study employed an integrated computational approach to evaluate the binding selectivity of KP-10 across key receptors implicated in impulsivity and compulsion. Three-dimensional structures of KP-10 bound to kisspeptin receptor 1 (KISS1R), neuropeptide FF receptor 1 (NPFF1R), dopamine D1/D2 receptors (D1R/D2R), and serotonin 5-HT1A/2A receptors (5-HT1AR/5-HT2AR) were predicted via AlphaFold2 and embedded in lipid bilayers for 500-ns molecular dynamics simulations. Binding free energies calculated via the implicit solvation method revealed the lowest binding energies for KISS1R (ΔG_GB =- 158.3 ± 6.9 kcal/mol), followed by NPFF1R (ΔG_GB =- 155.5 ± 10.0 kcal/mol), with substantially weaker interactions for 5-HT1AR (- 136.5 ± 9.2 kcal/mol), D2R (- 115.9 ± 9.5 kcal/mol), and 5-HT2AR (- 111.1 ± 9.3 kcal/mol). Conformational stability metrics (RMSD, RMSF, Rg, and hydrogen bond occupancy) corroborated these energetic trends. These results demonstrate the high selectivity of KP-10 for KISS1R compared to the following monoaminergic receptors: dopamine types 1 and 2 and serotonin types 1A and 2A, suggesting that its effects on impulsive and compulsive behavior occur primarily through canonical kisspeptin signaling rather than through direct modulation of these receptors. However, experimental confirmation of these results is required to draw firm conclusions.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00726-0.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"223"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational and experimental evaluation of curcumin as a DNMT3B-targeting epigenetic modulator in pancreatic cancer.","authors":"Ali Afgar, Saeed Zanganeh, Roohollah Mirzaee Khalilabadi, Tahereh Haghpanah, Mostafa Amopour Bahnamiry, Hoda Ebrahimi, Mohamad Javad Mirzaei-Parsa, Batoul Kavyani","doi":"10.1007/s40203-026-00717-1","DOIUrl":"10.1007/s40203-026-00717-1","url":null,"abstract":"<p><p>Pancreatic cancer remains a therapeutic challenge due to its aggressive nature and resistance to conventional therapies. This study investigates the epigenetic effects of curcumin on the miR-29b/DNMT3B/MUC1 axis in pancreatic cancer cells (MIA PaCa-2) through an integrated bioinformatics and experimental approach. In silico analyses, including molecular docking and a preliminary 10 ns molecular dynamics simulation, indicated a plausible binding pose of curcumin within DNMT3B's catalytic site (binding energy: - 4.72 kcal/mol), with key interactions at residues GLU585 and ASN718, suggesting short-term binding persistence. In vitro experiments demonstrated that curcumin (IC₅₀ = 32.1 μM) significantly upregulated miR-29b (1.27-fold, <i>p</i> < 0.05), downregulated DNMT3B (63% reduction) and MUC1 (78% reduction), and induced ROS-dependent apoptosis (240% increase in ROS at 60 μM, <i>p</i> < 0.0001). DAPI staining confirmed nuclear fragmentation and apoptotic body formation, while minimal toxicity was observed in normal HUVEC cells. ADMET analysis highlighted curcumin's favorable pharmacokinetic profile, including oral bioavailability (HIA ≈ 0.78) and low toxicity. These findings underscore curcumin's dual role as an epigenetic modulator (via miR-29b/DNMT3B/MUC1) and ROS inducer, offering a promising strategy for targeted pancreatic cancer therapy.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"226"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico design of a novel peptide-based vaccine candidate against <i>Streptococcus pneumoniae</i>.","authors":"Jahangir Sabzevari, Mona Shafaghi, Zohreh Bahadori, Zahra Nabizadeh","doi":"10.1007/s40203-026-00740-2","DOIUrl":"10.1007/s40203-026-00740-2","url":null,"abstract":"<p><p><i>Streptococcus pneumoniae</i> remains a leading bacterial pathogen causing pneumonia, meningitis, septicemia, and post-viral respiratory infections such as COVID-19. Despite licensed vaccines, efficacy is limited by serotype dependency, cost, and restricted coverage, highlighting the need for broad-spectrum alternatives. Protein-based vaccines with conserved antigens represent a promising strategy. This study aimed to design and evaluate an efficient peptide-based vaccine against pneumococcal virulence factors using immunoinformatics tools. Two major pneumococcal surface proteins were selected, and two immunodominant epitope-rich regions enriched in overlapping B-cell and MHC-II epitopes were identified and linked using a flexible linker. To enhance immunogenicity, human β-defensin-2 (hBD-2) was fused to the N-terminus with a rigid linker, and a His-tag was added at the C-terminus. The construct showed high predicted antigenicity (VaxiJen score: 0.917), was predicted to be non-allergenic, and exhibited favorable solubility and physicochemical properties. Structural modeling, refinement, discontinuous B-cell epitope mapping, docking with TLR4/MD2, molecular dynamics, and immune simulations were performed. The construct demonstrated favorable stability and safety, while B-cell epitope mapping indicated predicted immunogenic potential. Molecular docking predicted stable interactions with TLR4/MD2, with the top-ranked ClusPro complex showing an energy score of - 779.3. Normal mode analysis suggested structural flexibility and conformational stability of the complex. Immune simulations predicted potentially robust primary, secondary, and tertiary responses, including antibody production, memory cell generation, and IFN-γ induction. Integrating conserved immunodominant regions into a peptide-based construct with hBD-2 adjuvant through rational immunoinformatics resulted in a computationally predicted stable and immunogenic candidate that may potentially overcome serotype dependency and provide broader protection. In silico results suggest this peptide-based vaccine is a promising candidate, warranting further in vitro and in vivo validation.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00740-2.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"231"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based virtual screening, multi-score docking, and molecular dynamics simulation of novel small molecules targeting the epidermal growth factor receptor for potential management of oral squamous cell carcinoma.","authors":"Muhammad Bilal Azmi, Tehreem Zia, Uzma Asif, Sheikh Arslan Sehgal, Sadaf Naeem, Shamim A Qureshi, Syed Danish Haseen Ahmed, Fauzia Imtiaz","doi":"10.1007/s40203-026-00722-4","DOIUrl":"10.1007/s40203-026-00722-4","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is a major global health burden, with epidermal growth factor receptor (EGFR) serving as an important therapeutic target. However, resistance to currently available EGFR inhibitors limits the efficacy of long-term treatment. In this study, a structure-based virtual screening approach was employed using the Mcule database to identify novel small molecules with potential EGFR-inhibitory activity. The top-ranked compounds were subjected to consensus docking using multiple docking platforms and compared with established EGFR inhibitors. The most promising complexes were further evaluated using 500 ns molecular dynamics simulations to investigate their structural stability, conformational flexibility, and binding persistence. ADMET and pharmacokinetic analyses were performed to assess the drug-like and safety profiles. Five lead compounds (C1-C5) demonstrated significant binding affinities toward EGFR, ranging from - 9.9 to - 9.2 kcal/mol, while satisfying the major drug-likeness criteria. Molecular dynamics simulations suggested that C1 and C4 may form relatively stable EGFR-ligand complexes, as supported by stable RMSD convergence and persistent interactions with key active-site residues throughout the simulation period. Trajectory-based interaction analyses further indicated a sustained binding behavior. ADMET profiling predicted favorable oral bioavailability and low predicted toxicity for most compounds, particularly C3 and C5, although a potential risk of cytochrome P450-mediated drug-drug interactions was observed. Overall, the shortlisted compounds exhibited docking and dynamic stability profiles comparable to those of the reference inhibitor Lapatinib. These findings suggest the potential therapeutic relevance of structurally novel EGFR-targeting scaffolds in OSCC and provide a foundation for future experimental validation through in vitro and in vivo studies.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00722-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"220"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design of peptide ligands targeting transcription in <i>Helicobacter pylori</i>.","authors":"Judith Gracia, Balaji Nagarajan, Vyshnavi Manikam, Preethi Ragunathan","doi":"10.1007/s40203-026-00679-4","DOIUrl":"10.1007/s40203-026-00679-4","url":null,"abstract":"<p><p><i>Helicobacter pylori</i> colonize the gastric epithelial cells and poses a strong risk factor for gastric complications like chronic gastritis, ulcer diseases, and gastric cancer. Despite the complex treatment regimens, antibiotic resistance is the primary cause of eradication failure and calls for alternate treatment strategy. This study aims to design peptide ligands that specifically target protein-protein interactions in the transcription machinery of <i>H. pylori</i>. The dissociable σ-factor known as SigA, which binds with the RNA polymerase (RNAP) core beta-prime subunit (RpoC). This interacting region has been targeted to design specific peptide ligands using structure-based computational methods. The lack of experimental structures necessitated generating structural models for Hp RpoC, Hp SigA and Hp RpoC-SigA complex structure. The complex was built based on hybrid template-based modeling (TBM) techniques. The RpoC-SigA interface has been exploited to design five suitable peptides-three peptides from <i>H. pylori</i> SigA (P1, P2, and P3) and two peptides from the SigA-interacting regions of <i>H. pylori</i> RpoC (P4 and P5). Investigation of the binding affinity of all five peptides suggests that P1, P3, and P5 exhibit significant affinity, indicating a potential hindrance to RNAP interaction with transcription factors prior to holoenzyme formation. These peptides may serve as promising inhibitors against <i>H. pylori</i> infection.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00679-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"219"},"PeriodicalIF":0.0,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148901798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A description of the structural and functional impacts of the SCID- and OS-associated variants on RAG1 through MD simulations.","authors":"Asli Kutlu, Sinem Firtina, Begüm Işikgil","doi":"10.1007/s40203-026-00725-1","DOIUrl":"10.1007/s40203-026-00725-1","url":null,"abstract":"<p><p>The immune system is the body's defense mechanism that uses cells and organs to protect against foreign substances called pathogens. The absence or dysfunction of elements within immune system lead to immune diseases such as severe combined immunodeficiency (SCID). SCIDs are hereditary disorders that are characterized and sub-classified by an impaired number and function of T and B cells as T-B + SCID and T-B-SCID. The association between varied SCID phenotypes, including Omenn Syndrome, in clinics has been revealed with the presence of missense mutatinos in RAG1 gene. Here, we aim to understand the structural impacts of varied SCID phenotypes associated variants in RAG1 by utilizing in silico tools, molecular dynamics simulations and docking studies. Along 100 ns, classical MD simulations are run with mutant RAG1 complexes, including Arg396Leu(rs104894291), Arg396His(rs104894291), Val433Met(rs199474679), Met435Val(rs141524540), Arg474His(rs199474686), Arg474Cys(rs199474678), Trp522Cys(rs193922461), Glu722Lys(rs28933392), Arg778Gln(rs121918569), and Arg975Trp(rs121918570). Any structural alterations experienced in RAG1 due to presence of these missense variants were studied together with the change in RAG1-RAG2 protein-protein binding dynamics and 12-RSS heptamer/23-RSS nanomer bindings to RAG1 to understand the functional impacts of these missense variants on RAG1. These calculations have suggested that Arg396Leu(rs104894291), Arg474His(rs199474686), Arg474Cys(rs199474678), and Glu722Lys(rs28933392) have resulted in more drastic alterations in RAG1's structure and function compared to others. We ended up with the theoretical background constituted by molecular dynamics simulations and docking calculations for each SCID or atypic SCID (Omenn Syndrome). Our calculations would be further utilized to design a novel molecule or to run drug repurposing to ensure the proper functioning of mutant RAG1.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00725-1.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"218"},"PeriodicalIF":0.0,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the protective potential of <i>Aspilia africana</i> against phenanthrene-induced cardiorenal injury: biochemical and computational approaches.","authors":"Ayomide Israel Ajayi, Heritage Omoju, Ayomide Oyatoro, Jesupemi Deborah Temitope, Kemisola Mercy Ademoroti, Rukayat Olanrewaju, Adetunji Raymond Adeoti, Hephzibah Ogunlade, Mathew Wasiu Owonikoko, Kazeem Olasunkanmi Ajeigbe","doi":"10.1007/s40203-026-00721-5","DOIUrl":"https://doi.org/10.1007/s40203-026-00721-5","url":null,"abstract":"<p><p>Environmental exposure to phenanthrene (PHE), a polycyclic aromatic hydrocarbon, poses significant toxicological risks to vital organs, particularly the heart and kidney, through oxidative stress, inflammation, and apoptosis. This study evaluated the protective effects of <i>Aspilia africana</i> aqueous extract and chrysin against phenanthrene-induced cardiorenal toxicity in rats, while also exploring underlying molecular mechanisms using in silico approaches. Cardiorenal toxicity was induced by oral administration of phenanthrene for 26 days. Concurrent treatment groups received <i>Aspilia africana</i> (500 or 750 mg/kg) or chrysin (25 mg/kg). Renal and cardiac function biomarkers, oxidative stress indices, inflammatory cytokines, and apoptotic proteins were assessed in serum and tissue samples. Molecular docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses were performed to evaluate interactions of selected <i>Aspilia africana</i> phytochemicals with sodium-glucose cotransporter-1 (SGLT1) and glucagon-like peptide-1 receptor (GLP-1R). Phenanthrene exposure significantly elevated serum urea, creatinine, cystatin C, creatine kinase-MB, and cardiac troponins I and T, while suppressing antioxidant enzymes (SOD, CAT, GPx). Pro-inflammatory cytokines (IL-1β, TNF-α) and pro-apoptotic markers (caspase-3, Bax, p53) were upregulated, whereas IL-10 and Bcl-2 were reduced. Co-administration of <i>Aspilia africana</i> or chrysin markedly reversed these alterations, restoring antioxidant balance and attenuating inflammatory and apoptotic responses. Molecular docking revealed favourable binding affinities of bioactive phytochemicals with SGLT1 and GLP-1R, while ADMET profiling indicated acceptable drug-likeness and low predicted toxicity for most compounds. This study suggests the multi-target protective potential of <i>Aspilia africana</i> against phenanthrene-induced cardiorenal toxicity, integrating in vivo biochemical evidence with in silico molecular interactions to provide mechanistic insight into its therapeutic relevance in environmental toxicology.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-026-00721-5.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"214"},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-(-)-ribofuranose identified from traditional fermented rice beverages of Assam exhibits monoamine oxidase inhibitory activity: an integrated GC-MS/MS metabolomics, molecular docking, molecular dynamics, and in vitro study.","authors":"Rohit Das, Bipashna Thatal, Buddhiman Tamang","doi":"10.1007/s40203-026-00720-6","DOIUrl":"https://doi.org/10.1007/s40203-026-00720-6","url":null,"abstract":"<p><p>Traditional rice-based fermented beverages are recognized as rich sources of bioactive metabolites with potential therapeutic relevance for neurodegenerative disorders. GC-MS/MS metabolomics, molecular modeling, and in vitro assays were combined to identify and evaluate metabolites with potential monoamine oxidase inhibitory activity and a preliminary approach to identify potential anti-Alzheimer's compounds from traditional rice beverages. GC-MS/MS-based untargeted metabolomics revealed substantial metabolic diversity, with 166, 113, 145, and 123 metabolites detected in <i>black rohi</i> (BR), <i>sai mod</i> (SM), <i>jou bidwi</i> (JOU), and <i>rohi</i> (RH), respectively, and 93 metabolites shared across the fermented samples. Structure-based virtual screening of 99 compounds comprising metabolites and FDA compound, identified D-(-)-ribofuranose as a candidate metabolite showing favorable predicted interactions with MAO-A and MAO-B in molecular docking studies of - 9.5 kcal/mol (MAO-A) and - 10.2 kcal/mol (MAO-B) compared to the reference drug isocarboxazid (- 7.2 and - 7.6 kcal/mol, respectively). Molecular dynamics simulations conducted for 200 ns confirmed structural stability of the complexes, with the MAO-B-D-(-)-ribofuranose system showing low RMSD (0.26 ± 0.03 nm), stable radius of gyration (2.19 ± 0.02 nm), solvent-accessible surface area values comparable to those observed for the reference complex (195 ± 6 nm²), and increased hydrogen bonding (5.6 ± 1.2 bonds). Cytotoxicity evaluation using the SH-SY5Y cell line yielded an IC₅₀ value of 51.33 µM after 24 h exposure. Enzyme kinetics confirmed concentration-dependent inhibition of both MAO-A and MAO-B enzymes under the experimental conditions evaluated, supporting the potential of D-(-)-ribofuranose as a candidate monoamine oxidase inhibitory metabolite warranting further biochemical and pharmacological investigation.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-026-00720-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"215"},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coevolutionary analysis-driven design of a p53 neoantigen multi-epitope peptide vaccine for lung cancer immunotherapy.","authors":"Komal Kumari, Gyan Prakash Rai, Manaswini Jagadeb, Srishti Shriya, Nooruddin Khan, Vinay Kumar, Asheesh Shanker, Rizwanul Haque","doi":"10.1007/s40203-026-00700-w","DOIUrl":"https://doi.org/10.1007/s40203-026-00700-w","url":null,"abstract":"<p><p>Neoantigen (NeoAg)-based vaccines have emerged as promising immunotherapeutic approaches for lung cancer (LC) treatment. However, the high mutational variability of p53 protein poses challenges for durable vaccine design. In this study, we implemented a coevolution-guided immunoinformatics approach to design an epitope-based multi-epitope peptide vaccine targeting p53. We analyzed 224 homologous p53 sequences to identify coevolving amino acids using compensation and correlation methodologies. Compensation analysis identified 12 coevolving groups comprising 26 residues (6.6%), whereas correlation analysis revealed 14 groups involving 46 residues (11.7%), resulting in 39 evolutionarily constrained positions that were less prone to immune escape. Both B and T-cell epitopes were predicted and mapped onto these coevolving residues to select regions with high antigenicity and structural stability. Vaccine constructs (non-mutated and mutated (NeoAg) epitopes) were generated, modeled, and validated. In-silico expression of vaccine constructs in <i>E. coli</i> K12 showed promising results. Molecular docking with toll-like receptor 4 (TLR4) demonstrated a strong binding affinity (ΔG = - 15.5 kcal/mol). Furthermore, 200 ns molecular dynamics simulations confirmed the structural stability of both vaccine-TLR4 complexes, while immune simulations predicted robust humoral and cellular immune responses, particularly for the NeoAg construct. Population coverage analysis indicated broad applicability, covering 93.4% of global HLA alleles. This study introduces a novel coevolution-guided immunoinformatics framework for TP53-derived multi-epitope vaccine design, providing a promising strategy for LC immunotherapy. However, experimental validation needed to confirm its efficacy and safety.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-026-00700-w.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"217"},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of selective bioactive compounds from Fenugreek seed extracts by GC-MS analysis and their anti-tumoral potential via modulation of Parkin in oral cancer.","authors":"Rashmi Kumari, Madhu Rani, M Amarendar Reddy, Siya Ram, Imran Khan, M Moshahid Alam Rizvi","doi":"10.1007/s40203-026-00711-7","DOIUrl":"https://doi.org/10.1007/s40203-026-00711-7","url":null,"abstract":"<p><p>Oral cancer (OC) is a serious health concern globally. Various pieces of evidence have observed that the primary aetiology of OC in an individual is molecular-level dysregulation via several processes in multiple tumour suppressor genes (TSGs), including p53, PTEN, FOXO, and Parkin, leading to variations in their expression levels. Parkin, an E3 ubiquitin ligase, was primarily recognized as a gene implicated in autosomal recessive juvenile Parkinsonism; nonetheless, several studies show that Parkin is a TSG, involved in several malignancies. In the present study, we have first explored the role of Parkin against oral cancer. Current conventional anti-cancer therapies cause several harmful side effects, are costly in nature and also time-consuming. Therefore, it is crucial to explore alternative natural therapeutic approaches which can impede or slow the progression of OC by regulating TSG expression. In recent times, plant-derived bioactive compounds might be used as natural therapeutic approaches to curb OC by regulating TSGs. Using medicinal plants and their parts can be a reliable and efficient option with no or minimal side effects. Fenugreek is one of the nature-gifted plants that exhibits several health-beneficial properties, including anti-cancer. The current investigation primarily addressed the anti-cancer properties of bioactive compounds derived from Fenugreek seeds and their interaction with Parkin to combat OC, which remains unexplored. The current study employs various methods to examine the anti-tumor effects of ten bioactive compounds out of 75 constituents, including Gas Chromatography-Mass Spectrometry, in vitro studies, MTT assay, DNA fragmentation, and ELISA, while in-silico studies, ADME/T, molecular docking and dynamic simulation. The results show that Diosgenin exhibited drug-like attributes, which inhibited human KB cell proliferation (273.47 µg/mL) in 24 h and contained high binding affinity and a more stable complex with Parkin protein - 8.9kcal/molthanstandarddrug,Doxorubicin -8.0 kcal/mol inspected bydockingand H-bonds, RMSD, RMSF, RG, and SASA by simulation studies. These findings have revealed that OC treatment with Diosgenin may be a promising potent anti-cancer drug. Hence, current studies can be useful in the development of safe and non-toxic therapeutic regimen to prevent OC.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"212"},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}